Publication Date
3-15-2025
Journal
International Journal of Cancer
DOI
10.1002/ijc.35274
PMID
39635770
PMCID
PMC11738659
PubMedCentral® Posted Date
3-15-2026
PubMedCentral® Full Text Version
Author MSS
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with substantial disease heterogeneity, limited treatment options, and dismal clinical outcomes. Some TNBCs display homologous recombination deficiency (HRD), a phenotype with elevated genomic burden and worse prognosis if left untreated but chemotherapeutic sensitivity. While the molecular landscape of TNBC is distinct from other breast cancer subtypes, the TNBC-specific link between HRD and epigenome-wide methylation has not been established. This study reports two independent cohorts of TNBC tumors (n = 32 and n = 58) with HRD and epigenomic landscapes measured by the Multiplex Ligation-dependent Probe Amplification assay and the Illumina MethylationEPIC arrays, respectively. Genome-wide copy number and methylation alterations were significantly higher in HRD (all p < .05). Methylation of genome-wide repeat element Alu and transcriptional regulatory regions were significantly lower in HRD (all p < .05). An age-adjusted epigenome-wide association study of the continuous HRD probability scores revealed significant loci (all FDR < 0.05) that were depleted from the CpG-rich "island" regions often seen in gene promoters but enriched in the CpG-poor "open sea" regions localized to gene enhancers. The significant loci implicated well-known candidate genes involved in the epithelial-to-mesenchymal transition, Wnt signaling, and DNA damage response. Supervised machine learning of HRD with nucleotide-specific methylation as the input enabled clinically relevant tumor stratification. Taken together, this study provides novel biological and translational insights into HRD in TNBCs.
Keywords
Humans, Triple Negative Breast Neoplasms, Female, DNA Methylation, Homologous Recombination, Epigenomics, Middle Aged, Epigenesis, Genetic, Genome-Wide Association Study, Gene Expression Regulation, Neoplastic, DNA Copy Number Variations, Adult, Aged, BRCAness, breast cancer, epigenetics, homologous recombination deficiency, triple-negative breast cancer
Published Open-Access
yes
Recommended Citation
Chen, Youdinghuan; Salas, Lucas A; Marotti, Jonathan D; et al., "Extensive Epigenomic Dysregulation Is a Hallmark of Homologous Recombination Deficiency in Triple-Negative Breast Cancer" (2025). Faculty, Staff and Students Publications. 6936.
https://digitalcommons.library.tmc.edu/baylor_docs/6936